CREM-activated LTBP1 transcription promotes radioresistance and immune escape in triple-negative breast cancer

Although radiotherapy is one of the first-line treatments for triple-negative breast Cancer (TNBC), acquired radioresistance blunts its clinical efficacy. The current study sought to evaluate the effect of latent-transforming growth factor beta-binding protein 1 (LTBP1) on radioresistance in TNBC cells and to explore the molecular mechanism. Two TNBC-related GEO datasets (GSE120798 and GSE210306) were included to analyze the novel molecule involved in radioresistance. F-box/WD repeat-containing protein 7 (FBXW7) was reduced in radioresistant cells, whereas cAMP-responsive element modulator (CREM) and LTBP1 were elevated. CREM promoted LTBP1 transcription, while FBXW7 mediated the protein degradation of CREM in TNBC cells. LTBP1 knockdown repressed radioresistance of TNBC cells by reverting epithelial-mesenchymal transition and preventing TNBC cell escape from CD⁺ T and NK cell-mediated immune surveillance. The repressing effects of the knockdown of CREM on radioresistance and immune escape were reversed by overexpression of CREM. Elevated FBXW7 increased the radiosensitivity of TNBC cells in vitro and in vivo, and radioresistance was partially rescued after CREM upregulation. These results indicate that inhibition of protein degradation of CREM due to FBXW7 loss promotes radioresistance and immune escape in TNBC by increasing LTBP1 transcription, providing a new potential target for improving radiotherapy sensitivity in TNBC.

CREM; FBXW7; LTBP1; Radioresistance; Triple-negative breast cancer.